Intravenous fenoldopam in heart failure: comparing the hemodynamic effects of dopamine1 receptor agonism with nitroprusside

Dopamine1 receptors mediate hemodynamic effects that may be beneficial in patients with congestive heart failure. We infused the selective dopamine1 receptor agonist, fenoldopam mesylate (SKF 82526 J), to evaluate hemodynamic and neurohumoral changes during continuous intravenous infusion in patients with congestive heart failure and compared them with the effects of nitroprusside, a traditional vasodilator that works by a distinctly different mechanism. In 15 patients with a mean radionuclide ejection fraction of 17%, the agents were infused in a random-ordered, double-blinded, crossover, active drug-controlled protocol after optimal dosing was determined during a titration period. Hemodynamic changes were induced in minutes with both drugs during a mean (+/- standard deviation) infusion dose of 1.45 +/- 1.66 micrograms/kg/min for fenoldopam and 2.99 +/- 1.59 micrograms/kg/min for nitroprusside. At 1 hour, mean blood pressure decreased and cardiac index rose with both drugs, and the effect lasted throughout the 6-hour infusion period. Nitroprusside, but not fenoldopam, reduced right heart filling pressures (including mean pulmonary capillary wedge, mean right atrial, and mean pulmonary artery pressures) during the infusion period. Both drugs caused significant reduction in systemic vascular and pulmonary arteriolar resistances. No significant change occurred in plasma norepinephrine levels. Fenoldopam ameliorates some of the adverse hemodynamic changes that occur during heart failure but does not reduce right heart filling pressures as does nitroprusside. Because of fenoldopam's unique characteristics, it may benefit certain patients with heart failure.     

Effects of dopamine DA1-receptor blockade and angiotensin converting enzyme inhibition on the renal actions of fenoldopam in the anaesthetized dog.

Experiments were performed in anaesthetized dogs to characterize the renal effects of the selective dopamine DA1-receptor agonist, fenoldopam. Intrarenal artery infusion of fenoldopam (0.01-10 micrograms/kg per min) caused dose-related renal vasodilation. At low doses (0.01-0.3 micrograms/kg per min), renal vasodilation occurred without concomitant falls in blood pressure but was accompanied by increased urine output. This diuresis was most probably a result of reduced tubular reabsorption since glomerular filtration rate was not increased. Both fenoldopam-induced renal vasodilation and diuresis were blocked to a similar extent by the selective dopamine DA1-receptor antagonist, SCH 23390 (30 micrograms/kg, intravenously), suggesting that both effects were mediated by dopamine DA1-receptors. In the presence of the angiotensin converting enzyme inhibitor, captopril (1 mg/kg, intravenously, + 20 micrograms/kg per min, intrarenal artery), fenoldopam (0.01-0.3 micrograms/kg per min) significantly increased fractional excretion of sodium, despite reducing blood pressure; neither of these effects were observed in captopril-free dogs. These observations support the view that the inhibitory effect of fenoldopam on tubular function, and its vasodepressor activity, may be opposed by angiotensin II resulting from fenoldopam-induced renin release.     

Selective dopamine DA1 stimulation with fenoldopam in cirrhotic patients with ascites: a systemic, splanchnic and renal hemodynamic study.

We studied the effects of fenoldopam, a selective dopamine DA1 agonist on systemic and splanchnic hemodynamics, renal blood flow and sodium excretion in 12 patients with alcoholic cirrhosis and ascites. Hepatic, azygos and renal veins were catheterized before and after intravenous administration of fenoldopam, 0.05 micrograms/kg/min for 1 hr and increased to 0.1 micrograms/kg/min for another hour. Mean arterial pressure progressively decreased (from 83 +/- 7 to a minimum of 77 +/- 8 mm Hg 100 min after starting the infusion) but returned to baseline level at 120 min. Plasma norepinephrine and renin activity increased (respectively from 567 +/- 297 to 919 +/- 375 pg/ml, p less than 0.05, and from 17 +/- 14 to 23 +/- 15 ng/ml/hr, p less than 0.05). Renal blood flow, urine output or sodium excretion did not change. Sodium output decreased at 1 hr from 6.9 mumol/min to 4.0 mumol/min, p less than 0.05. Both hepatic venous pressure gradient and azygos blood flow significantly increased by 21%. We conclude that the acute administration of fenoldopam did not improve renal hemodynamics or function in patients with cirrhosis and ascites. In addition, dopamine DA1 agonism caused further increases in norepinephrine concentration and plasma renin activity. Portal pressure also increased, probably because of an increase in mesenteric blood flow. These results question the renal benefit and raise concern about the use of dopamine agonists in patients with cirrhosis and ascites.     

Effects of fenoldopam,a dopamine D-1 agonist,and clevidipine,a calcium channel antagonist,in acute renal failure in anesthetized rats

The present studies were conducted to: a) comparatively evaluate the effects of clevidipine, a new dihydropyridine calcium antagonist, and fenoldopam, a dopamine (D-1) receptor agonist on basal renal function, and b) to determine the efficacy of these agents in protecting renal function in an experimental model of ischemia/reperfusion (I/R) induced acute renal failure in rats. Infusions of either clevidipine or fenoldopam (5.0 nmol/kg(-1) min(-1) i.v. for 60 min) produced significant increases in urine flow (UV), urinary sodium excretion (UNaV), and fractional excretion of sodium (FENa) in inactin anesthetized rats. Unlike clevidipine, fenoldopam also produced significant increases in renal blood flow (RBF) and urinary potassium excretion (UKV). In a separate series, unilateral renal failure was induced in anesthetized rats by occluding the left renal artery for 40 min followed by reperfusion. In this model, there was a 70-75% reduction in the GFR that was paradoxically associated with several fold increases in UV, UNaV, and FENa in the vehicle treated group. In two separate groups, infusions of neither clevidipine nor fenoldopam (5.0 nmol/kg(-1) min(-1)) for 60 min beginning 10 min before reperfusion, improved filtration fraction. However, clevidipine treatment markedly improved tubular function in that loss of sodium and water were significantly attenuated and UV and UNaV were restored towards basal levels. In contrast, in the fenoldopam group, tubular function was further deteriorated as evidenced by exacerbated losses of sodium and water. These observations suggest that whereas both clevidipine and fenoldopam were potent natriuretic agents, only the calcium antagonist was effective in preserving renal function in the present experimental model of ischemic renal failure.     

Cardiovascular risk profile with the new immunosuppressive combinations after renal transplantation

Cardiovascular disease remains the main cause of death among kidney transplant patients. Cardiovascular risk burden already present at the moment of transplantation is substantially worsened by chronic use of immunosuppressants. On the other hand, chronic allograft nephropathy, a clinical-pathological result of immunological and non-immunological damage of the graft, is the main cause of graft loss in the long-term. Among the non-immunological factors contributing to the development of chronic allograft nephropathy, cardiovascular risk factors also seem to play a role. In the present review, we analyse the impact of the different immunosuppressive medications on cardiovascular risk factors after renal transplantation, including renal function.     

Comparison of dopamine and fenoldopam effects on renal blood flow and prostacyclin excretion in normal and essential hypertensive subjects

We recently reported that a low dose dopamine (DA) infusion in normal subjects increased renal blood flow (RBF) via prostacyclin (PGI2) formation without changes in PGE2 levels. The present study explores whether this mechanism is mediated by the DA1 receptor and evaluates the effect of DA on RBF and PGs in subjects with essential hypertension (EH). A low dose of DA (1 microgram/kg.min), which previously did not alter hemodynamics in normal subjects was infused into eight patient with EH to determine the role of DA stimulation in hypertensives. To assess the effect of DA1 stimulation, fenoldopam, a selective DA1 agonist, was infused (0.1 microgram/kg.min) into 10 normal and 10 hypertensive patients. Fenoldopam, unlike DA, significantly decreased diastolic blood pressure in hypertensives (96 +/- 3 to 85 +/- 2 mm Hg; P less than 0.01) along with a significant increase in pulse rate (68 +/- 2 vs. 73 +/- 2 beats/min; P less than 0.01). RBF measured by para-aminohippurate clearance increased only in normals during fenoldopam infusion from 1185 +/- 71 to 1533 +/- 84 L/min.m2 (PGI(2)01), and this was associated with an increase in PGI2 (6-keto-PGF1) excretion (149 +/- 19 vs. 214 +/- 32 ng/g creatinine; P less than 0.02). These effects of fenoldopam were similar to DA effects on RBF and PGI2 excretion in normals. In contrast, in hypertensive subjects, neither fenoldopam (867 +/- 113 vs. 1054 +/- 177 L/min.m2; P greater than 0.1) nor DA (1098 +/- 85 vs. 1061 +/- 101 L/min.m2; P greater than 0.1) increased RBF. Similarly, neither the DA nor the fenoldopam infusion stimulated PGI2 excretion in the hypertensives. The fenoldopam infusion in the hypertensives produced a significant natriuresis (22 +/- 3 to 49 +/- 9 mmol/3 h; P less than 0.05). Similar effects on Na+ excretion in this group were noted during DA infusion (17 +/- 3 to 36 +/- 3 mmol/3 h; P less than 0.05), suggesting that DA-induced natriuresis is not directly linked to DA-induced changes in RBF or PG excretion. The present study shows that in normal subjects, fenoldopam, a specific DA1 agonist, like DA, stimulates renal PGI2 release and RBF. In contrast, neither DA nor fenoldopam alters PGI2 or RBF in patients with EH, suggesting an alteration of dopaminergic tone in some hypertensives that is characterized by a defect in DA1 receptor sensitivity.     

Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine1 agonist fenoldopam

Activation of dopamine1 (DA1) receptors relaxes vascular smooth muscle, especially in the renal vascular bed. Fenoldopam, the first selective DA1-receptor agonist that can be administered to man, was infused intravenously in 17 patients with essential hypertension (mean blood pressure 152/101 mm Hg). It reduced blood pressure in a dose-dependent fashion at doses between 0.025 and 0.5 microgram/kg/min and the antihypertensive effect was sustained during 2 hr infusions. In 10 patients studied during free-water diuresis, fenoldopam increased renal plasma flow by 42%, glomerular filtration rate by 6%, and sodium excretion by 202%, while lowering mean arterial pressure by 12% (all p less than .05). Similar promotion of sodium excretion was observed during blood pressure reduction in six additional patients studied without water loading. Pronounced enhancement of renal function in spite of blood pressure reduction suggests that fenoldopam might have a special role in the treatment of patients with hypertension and renal impairment.     

Cardiovascular risk profile in patients with myelopathy associated with HTLV-1

HAM/TSP (HTLV-1-associated myelopathy/tropical spastic paraparesis) is a slowly progressive disease, characterized by a chronic spastic paraparesis. It is not known if the disease carries an independent risk for cardiovascular disease. The objective of this study was to evaluate the cardiovascular risk profile related to HAM/TSP and compare it with the general population.

Selective dopamine-1 receptor agonist augments regional myocardial blood flow: comparison of fenoldopam and dopamine.

A new class of vasodilators exhibiting selective dopamine-1 receptor agonist activity is being introduced into clinical practice. Inasmuch as various vasodilators either augment or decrease myocardial blood flow ("coronary steal") depending on their pharmacologic action, the goal of this study was to assess the effects of fenoldopam (selective dopamine-1 receptor agonist) and dopamine (nonselective dopamine-1 receptor agonist) on regional myocardial blood flow in the presence of coronary occlusion. Accordingly, in 16 dogs anesthetized with pentobarbital, the left anterior descending coronary artery was occluded. Cardiovascular and renal hemodynamic effects were measured before and after intravenous infusion of renal equipotent doses of either fenoldopam (n = 9, 0.1 micrograms/kg/min) or dopamine (n = 7, 1 micrograms/kg/min). Both fenoldopam and dopamine caused a significant and comparable increase in renal blood flow. Fenoldopam but not dopamine significantly decreased the calculated peripheral vascular resistance and subsequently increased cardiac output. Dopamine had no effect on regional myocardial blood flow. In contrast, fenoldopam augmented transmural myocardial blood flow in normal (from 114 +/- 10 to 188 +/- 27 ml/100 gm/min, p less than 0.02) and ischemic border myocardium (from 45 +/- 5 to 68 +/- 11 ml/100 gm/min, p less than 0.03 and p less than 0.02 vs dopamine). There was a significant increase in blood flow to both the endocardial and epicardial layers of normal and ischemic border myocardium. These changes were accompanied by a significant reduction in coronary vascular resistance in the normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of fenoldopam on renal haemodynamics and natriuresis in chronic renal failure

The effect of oral administration of fenoldopam, a dopamine-1 receptor agonist, on blood pressure, renal haemodynamics and natriuresis was studied in 12 patients with chronic renal insufficiency. In addition, the effect of administering a low intravenous dose of fenoldopam on top of the oral dose was compared with the effect of the same intravenous dose given immediately before oral fenoldopam. Oral administration of fenoldopam (50 mg t.i.d. for 3 +/- 1 days followed by 100 mg t.i.d. for 8 +/- 1 days) induced a significant fall in blood pressure (median MAP from 107 to 101 mm Hg). Compared to baseline values, body weight, effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and fractional sodium excretion remained unchanged. Infusion of fenoldopam (0.05-0.1 micrograms/kg/min) on day 1 led to a significant fall in blood pressure (median mean arterial pressure from 107.0 to 98.5 mm Hg), and a significant rise in effective renal plasma flow (median ERPF from 132 to 146 ml/min/1.73 m2). Median fractional sodium excretion increased significantly from 2.1 to 3.3%. GFR, filtration fraction and plasma aldosterone concentration did not change. No relationship was found between the fenoldopam-induced changes in ERPF and natriuresis, nor between baseline GFR or ERPF and fenoldopam-induced urinary sodium loss. Infusion of fenoldopam while patients were on oral fenoldopam had no effect on blood pressure, ERPF or GFR. However, again natriuresis was induced, which did not differ significantly from the fenoldopam-induced natriuresis on day 1. We conclude that oral fenoldopam has a moderate blood pressure lowering effect in patients with chronic renal insufficiency, but exerts no effect on ERPF or GFR. Secondly, a fenoldopam-induced natriuresis does not appear to be related to changes in ERPF or aldosterone secretion.     

Cardiovascular circulatory adjustments and renal function in acute heart failure

This study aims to clarify the neurohumoral regulation of cardiovascular circulatory adjustments and to analyze changes in renal function and their relationship to cardiovascular hemodynamics in the early stage of heart failure. Cardiac and peripheral (calf segment) hemodynamics, neurohumoral factors and renal function were investigated in totally 139 patients with acute myocardial infarction (AMI). Capacitance vessel constriction was observed in patients with uncomplicated AMI (Killip-I, Forrester HS-I) and constriction of capacitance and resistance vessels in patients complicated by heart failure (Killip II, Forrester HS-II) or cardiogenic shock (Killip III-IV, Forrester HS-IV). Augmented sympathoadrenal discharge significantly related to the degree of pump dysfunction (elevation of heart rate, central venous pressure, pulmonary capillary wedge pressure (PCWP) and decrease of stroke volume index (SVI] and activation of the renin-angiotensin-aldosterone system significantly related to fall in tissue perfusion pressure (mean blood pressure and calf vascular resistance) would be a possible mechanism for these compensatory mechanisms. However these would contribute to excessive vasoconstriction in limbs resulting in exercise intolerance or renal glomerular function impairment. The derangement of creatinine clearance, serum creatinine (Scr), blood urea nitrogen and beta 2-microglobulin were related to Killip classification, and it was clarified that PCWP tended to elevate more in patients with preexisting renal function disturbance, and when cardiac output (CO) depressed much lower, reduction of CO per se caused more severe prerenal renal insufficiency. That is, there were significant correlations between renal function parameters and cardiovascular hemodynamics. The Cardio-Renal Subset (CRS) was originally developed according to the initial SVI and Scr, and it was demonstrated that the CRS would be of definite predictive value in early identification of high risk patients.     

Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency

In phase 1 of this study, 60 patients undergoing coronary angioplasty were randomized to receive saline, dopamine, or aminophylline; the overall incidence of contrast-induced renal failure was 38%, without difference among the 3 groups. In phase 2 of this study, 72 patients with established contrast-induced renal failure were randomized to receive saline or dopamine; dopamine had a deleterious effect on the severity of renal failure, prolonging the course.     

Action of fenoldopam, a selective dopamine (DA1) receptor agonist, on isolated human arteries

The effects of a DA1 dopamine receptor selective agonist, fenoldopam, were examined on human blood vessels. Fenoldopam relaxed precontracted human arteries in vitro from brachial, cerebral, cervical, colic, coronary, lumbar, pulmonary, renal and splenic sites. Fenoldopam failed to relax uterine or external iliac arteries or saphenous vein segments. These effects of fenoldopam were not endothelium dependent, but were antagonised by the selective DA1 receptor antagonists, SCH 23390, (+)-butaclamol, and (R)- more than (S)-sulpiride. The effect of fenoldopam may involve cyclic adenosine monophosphate. These studies indicate the presence of DA1 receptors on a variety of large isolated human arteries.     

Differences in AT2 -receptor stimulation between AT1 -receptor blockers valsartan and losartan quantified by renal interstitial fluid cGMP

OBJECTIVE : Angiotensin II-receptor blockers are an established class of antihypertensive agents, but the differences between individual members of the class are largely unknown. The present study employed an animal model to demonstrate angiotensin II-receptor blocker-specific effects and to quantify these differences by comparing two common agents, losartan and valsartan. METHODS : We measured the effects on angiotensin II AT2-receptor-mediated renal cGMP by microdialysis in the outer renal cortex in conscious normotensive, sodium-depleted, 4-week-old Sprague-Dawley rats. Rats (n = 8) were given equimolar and equidepressor doses of losartan (0.02 mmol/kg) or valsartan (0.02 mmol/kg) either intravenously or orally. Time was allowed for the conversion of losartan into its active metabolite, EXP 3174. RESULTS : Both drugs had equal effects on blood pressure. There were significantly greater increases in cGMP levels after administration of valsartan than of losartan with both routes of administration. Intravenous administration of valsartan led to a 69.1% increase in cGMP, versus a 10.3% increase with losartan. Five hours after oral administration of valsartan, a 48% increase in cGMP was observed versus a 10.9% increase with losartan. The increase after oral administration of valsartan was sustained 8 h after administration, whereas the effect of losartan was not sustained. The effects of losartan and valsartan on cGMP were completely inhibited by AT2-receptor blockade. CONCLUSION : The results indicate that AT1-receptor blockade with valsartan influences AT2-receptor-mediated angiotensin II responses to a greater extent than with losartan, as quantified by renal interstitial fluid cGMP.     

Hemodynamic effects of an oral dopamine receptor agonist (fenoldopam) in patients with congestive heart failure

Dopamine receptor stimulation causes vascular and neurohumoral responses that may be beneficial in patients with heart failure. Oral inactivity, emesis and adrenergic-induced arrhythmias have limited the use of currently available compounds. Fenoldopam (SKF-82526-J) is a new, orally available, selective, dopamine-receptor agonist with potent renal vasodilating properties (six times that of dopamine) without positive inotropic or adrenergic activity. Drug efficacy was clinically evaluated in 10 patients with heart failure after single oral doses of placebo and 50, 100 and 200 mg of medication. Placebo produced no changes. Peak efficacy was noted 30 minutes to 1 hour after the 200 mg dose with mean blood pressure decreasing from 96 +/- 15 (mean +/- SD) to 83 +/- 8 mm Hg (p less than 0.05), pulmonary capillary wedge pressure decreasing from 23 +/- 6 to 20 +/- 8 mm Hg (p less than 0.05) and mean pulmonary artery pressure decreasing from 32 +/- 9 to 29 +/- 8 mm Hg (p less than 0.05). Systemic vascular resistance decreased from 1,987 +/- 887 to 1,191 +/- 559 dynes.s.cm-5 (p less than 0.05) with a subsequent 55% increase in cardiac index from 2.2 +/- 1.1 to 3.1 +/- 1.3 liters/min per m2 (p less than 0.05). Heart rate and right atrial pressure did not change (p greater than 0.05). No emesis or new tachycardia was noted at any dose. Baseline hemodynamics generally returned within 3 to 4 hours. Fenoldopam, therefore, is a short-acting, orally effective drug that decreases systemic vascular resistance and increases cardiac index in patients with heart failure and represents a new class of oral compounds that may be useful in treating such patients.